Method for preparing α-arylpropionic acids

Abstract

Process for preparing alpha -arylpropionic acids by catalytically asymmetrically hydrogenating alpha -arylpropenoic acids prepared from alpha -aryl ketones.

What is claimed is: 
     
       1. Process for preparing naproxen comprising: a) electrochemically carboxylating 2-acetyl-6-methoxy-naphthalene to afford 2-(6'-methoxy-2'-naphthyl)-2-hydroxypropionic acid;   b) dehydrating the 2-(6'-methoxy-2'-naphthyl)-2hydroxypropionic acid of step a) to afford 2-(6'-methoxy-2'-naphthyl)propenoic acid; and   c) catalytically asymmetrically hydrogenating the 2-(6'-methoxy-2'-naphthyl) propenoic acid of step b).   
     
     
       2. Process of claim 1 wherein Step b) is conducted in a low molecular weight carboxylic acid selected from acetic acid and propionic acid. 
     
     
       3. Process of claim 1 wherein Step c) is conducted utilizing a ruthenium asymmetric hydrogenation catalyst at a temperature of less than about 30° C. 
     
     
       4. Process of claim 3 wherein the catalyst is represented by the formula:   [Ru(BINAP)XY].sub.n     wherein X and Y represent a nonchelating anionic ligand or a noncoordinating anion.   
     
     
       5. Process of claim 3 wherein the temperature is less than about 15° C. 
     
     
       6. Process of claim 1 wherein said 2-acetyl-6-methoxynaphthalene is obtained by a Friedel Crafts acylation of 2-methoxynaphthalene. 
     
     
       7. Process of claim 6 wherein said 2-methoxynaphthalene is obtained by Williamson ether synthesis utilizing a methylating agent and 2-hydroxynaphthalene. 
     
     
       8. A process for preparing an α-arylpropionic acid comprising: (a) electrochemically carboxylating an α-arylketone to produce an 2-aryl-2-hydroxypropionic acid,   (b) dehydrating said 2-aryl-2-hydroxypropionic acid to produce an α-arylpropenoic acid, and   (c) catalytically asymmetrically hydrogenating said α-arylpropenoic acid to produce said α-arylpropionic acid.   
     
     
       9. The process of claim 8 wherein the dehydration of said 2-aryl-2-hydroxypropionic acid is conducted in a low molecular weight carboxylic acid selected from the group consisting of acetic acid and propionic acid. 
     
     
       10. The process of claim 8 wherein the catalytic asymmetric hydrogenation of said α-arylpropenoic acid is conducted utilizing a ruthenium asymmetric hydrogenation catalyst selected from the group consisting of optically active bisphosphine binaphthyl compounds of the formula Ru(BINAP)(OCOR) 2 , Ru x  H y  Cl z  (BINAP) 2  (S) p  and [Ru(BINAP)XY] n , wherein BINAP represents a tertiary phosphine of the formula: ##STR7## R represents substituted and unsubstituted alkyl radicals having 1 to about 6 carbon atoms, substituted and unsubstituted halogenated alkyl radicals having 1 to about 6 carbon atoms, and substituted or unsubstituted aryl, arylkyl and arlkaryl radicals, R' represents hydrogen, substituted or unsubstituted alkyl radicals having 1 to about 6 carbon atoms, and substituted or unsubstituted aryl, aralkyl and alkaryl radicals, S is a tertiary amine, X and Y independently represent a nonchelating anionic ligand or a noncoordinating anion, y is 0 or 1, and when y=0, x=2, z=4 and p=0 or 1, and when y=1, x=1, y=1 and p=0, and wherein said catalytic asymmetric hydrogenation is conducted at a temperature of less than about 30° C. 
     
     
       11. The process of claim 10 wherein said catalytic asymmetric hydrogenation is conducted in the presence of a base. 
     
     
       12. The process of claim 10 wherein said catalyst is represented by the formula: [Ru(BINAP)XY] n  wherein X and Y independently represent a nonchelating anionic ligand or a noncoordinating anion. 
     
     
       13. The process of claim 10 wherein said temperature is less than about 15° C. 
     
     
       14. The process of claim 8 wherein said α-arylpropionic acid is selected from the group consisting of naproxen, ibuprofen, ketoprofen, pirprofen, fenoprofen, suprofen, flurbiprofen, benoxaprofen and carprofen. 
     
     
       15. The process of claim 14 wherein said α-arylpropionic acid is selected from the group consisting of naproxen and ibuprofen.